tbuckley/cabot-search huggingface dataset:
Camrelizumab in combination with apatinib as a perioperative treatment for patients with hepatocellular carcinoma at high risk of recurrence: A prospective, single-arm, phase 2 study.
Authors: Yunlong Cui, Xu Bao, Ge Yu, Huikai Li, Feng Fang, Qiang Li, Wei Zhang, Qiang Wu, Lu Chen, Chen Liu, Tianqiang Song
Journal: Journal of Clinical Oncology (2023)

4120 Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, and a rising cause of cancer-related mortality. To date, the optimal perioperative treatment strategy for HCC patients remains unclear. It is urgent to develop novel and reliable therapeutic interventions to reduce the risk of recurrence and improve survival in patients with locally advanced HCC. Methods: This prospective, exploratory, single-arm, phase 2 study enrolled patients with primary resectable HCC who had not received prior systemic therapy. Before surgery, patients received combination treatment with four cycles of camrelizumab (200 mg, Q2W) plus apatinib (250 mg, QD). Each cycle was two weeks. The feasibility of hepatic resection was assessed by radiographic imaging. After 4-8 weeks of surgery, patients continued combination therapy (camrelizumab [200 mg, Q2W] and apatinib [250 mg, QD]) for one year. Primary endpoint was major pathological response (MPR). Secondary endpoints were pathologic complete response rate (pCR), objective response rate (ORR), disease-free survival (DFS), and safety. Exploratory endpoint was microvascular invasion (MVI). This study is registered on Clinical Trials.gov, number NCT04701060. Results: Between Jan 12, 2021, and Aug 17, 2022, 31 patients with a median age of 54 years were enrolled. Among these, 21 patients (67.7%) had hepatitis B virus infection. Before surgical incision, two patients withdrew informed consent. Therefore, ORR based on RECIST 1.1 and mRECIST were 13.8% (4/29) and 48.3% (14/29), respectively. 26 patients underwent hepatic resection, R0 resection rate was 100%, 10 (38.5%) patients achieved MPR, and pCR rate was 7.7%. The reasons for patients not undergoing surgery were disease progression and serious adverse events (AEs). Among patients with MVI, M0 was found in 57.7% (15/26) patients, MI was found in 34.6% (9/26) patients, and M2 was found in 7.7% (2/26) patients. 1-year DFS rate was 77.4%, and median DFS was not reached. The most common AEs included increased aspartate aminotransferase (74.2%), increased alanine aminotransferase (70.1%), decreased platelet count (61.3%), anemia (58.1%), and decreased lymphocyte count (51.6%). Grade 4 AEs occurred in 7 of 31 patients, and there were no treatment-related deaths. Conclusions: Camrelizumab plus apatinib as a perioperative treatment is effective and tolerable in patients with HCC at high risk of recurrence. Preoperative neoadjuvant therapy has reduced the rate of MVI. Because of the short follow-up period, whether perioperative treatment can effectively reduce recurrence rates and improve long-term survival still needs further investigation. Clinical trial information: NCT04701060 .
Comparative efficacy and safety of anti-PD-1/L1 antibody plus anti-VEGF antibody and anti-PD-1/L1 antibody plus VEGFR-targeted tyrosine kinase inhibitor as first-line therapy for unresectable hepatocellular carcinoma (uHCC): A systematic review and network meta-analysis.
Authors: Ying Jieer, Yiwen Zhuo, Jingjing Li, Beibei Lu, Yuxi Zheng
Journal: Journal of Clinical Oncology (2023)

e16148 Background: Anti-PD-1/L1 antibody combined with anti-VEGF antibody and anti-PD-1/L1 antibody combined with VEGFR-targeted tyrosine kinase inhibitor are both effective first-line therapies for uHCC in clinical practice widely. However, direct comparisons across the two regimens are not available. We conducted a network meta-analysis of them in terms of overall survival (OS), progression free survival (PFS), objective response rate (ORR) and incidence of treatment-related adverse events (TRAEs). Methods: After a literature research performed in PubMed, MEDLINE, Embase, the Cochrane library and several major scientific societies from January 1 2007 to November 6 2022, 3,279 records were obtained. 6 phase III trials has been identified for the final analysis: REFLECT, IMbrave150, ORIENT-32, COSMIC-312, Qin 2022 and LEAP-002. The experiments were broadly classified into three groups: anti-PD-1/L1 antibody + anti-VEGF antibody (IMbrave150 and ORIENT-32), anti-PD-1/L1 antibody + VEGFR-targeted tyrosine kinase inhibitor (COSMIC-312, Qin 2022 and LEAP-002) and intermediate reference group (lenvatinib vs sorafenib, REFLECT). We derived hazard ratios (HR) with 95% confidence intervals (95%CI) for OS and PFS, odds ratio (OR) for ORR and relative risks (RR) for all grade and grade ≥3 TRAEs. With fixed effect models to estimate the indirect pooled HRs, ORs, RRs and 95%CI, a frequentist network meta-analysis was conducted using sorafenib as intermediate reference. Results: 4,012 patients were included in the analysis overall, among them, 1815 patients were treated with anti-PD-1/L1 antibody+VEGF-antibody (A+A), 1,099 patients were treated with anti-PD-1/L1 antibody+VEGFR-TKI (A+T), 877 patients were treated with lenvatinib (LEN) and 1,320 patients were treated with sorafenib (SOR). With a p-score of 98%, the combination of A+A provided the greatest reduction in the risk of death, was not significantly different from A+T (HR=0.84, 95%CI: 0.66-1.06). Besides, A+T were associated with the greatest effect in prolonging PFS and improving ORR with 91% for p-score, but there are no statistical differences with A+A (HR=1.06, 95%CI: 0.87-1.30, OR=0.82, 95%CI: 0.47-1.46). Considering the risk of TRAEs, A+A were significantly safer than A+T (RR=0.91, 95%CI: 0.84-0.98) in all grade of TRAEs and ≥3 grade (RR=0.91, 95%CI: 0.84-0.98). Conclusions: The combination of anti-PD-1/L1 antibody and anti-VEGF antibodies has the greatest probability of delivering the longest OS, while anti-PD-1/L1 antibody plus VEGFR-targeted tyrosine kinase inhibitor is correlated with larger PFS benefit at the cost of a lower safety rate.
Therapeutic potential of dual CDK12 and 13 inhibition in colorectal cancer.
Authors: Erdem Altunel, Mohammad Zokaasadi, Jason A. Somarelli, Shannon J. McCall, Patan Gultawatvichai, Giles Francis Whalen, Jason Pitarresi, David S. Hsu
Journal: Journal of Clinical Oncology (2023)

e15601 Background: To date, studies on cyclin-dependent kinase inhibitors in colorectal cancer (CRC), such as targeting CDK4/6 with Palbociclib, have shown little to no clinical benefit. However, tumor profiling of CRC has shown that mutations and amplifications in CDK 12 and 13 are prevalent in 5 to 10% of CRC patients, suggesting that CDK12/13 inhibition may be a potential target for patients with CRC. Methods: To study the effects of inhibiting CDK12 and 13 in CRC, a total of 11 patient-derived organoids (PDO) were first established from patients undergoing biopsy or resection of their primary or metastatic CRC. In vitro drug sensitivity assays were performed by treating each PDO with THZ531, a selective dual CDK12/13 inhibitor; 5-flurouracil, oxaliplatin and SN38 as a standard of care; or Palbociclib (CDK 4/6 inhibitor) at seven different drug concentrations (0.0064 μM - 100 μM) with five replicates at each concentration. Viability was assessed 72 hours following the addition of each drug using CellTiter-Glo (Promega) and IC 50 s were calculated. Results: Targeting CDK12/13 with THZ531 demonstrated dose dependent activity in the majority of CRC PDOs, with IC 50 values ranging from 0.06 μM to 4.2 μM. In comparison, targeting CDK4/6 with Palbociclib was ineffective, with IC 50 values ranging from 2.5 μM to 17 μM (p = 0.0003, 95% CI 3.7 to 10.4). Inhibition of CDK12/13 was also more effective than standard of care chemotherapy with either 5- FU or oxaliplatin (mean IC 50 values were 4.2 μM and 21.4 μM for 5-fluorouracil and oxaliplatin, p &lt; 0.05) and was comparable to irinotecan (mean IC 50 was 0.07 μM for SN38). Finally, no significant correlation was found between sensitivity to THZ531 and microsatellite status, mutations in RAS and BRAF, or grade of the original patient tumor. Conclusions: We identify dual CDK12/13 inhibition as a promising therapy to treat CRC. Further studies will focus on characterizing mechanisms of action, evaluating efficacy and toxicity in vivo, and determining biomarkers of response based on actionable genomic alterations.
Effect of system analysis of reactive oxygen species on prognosis and treatment decisions for patients with esophageal squamous carcinoma.
Authors: Qiang Lu, Qi Yang, Jinbo Zhao, Guizhen Li, Jipeng Zhang, Chenghui Jia, Gang Ji, Yi Wan, Yan Chen
Journal: Journal of Clinical Oncology (2023)

e16005 Background: The prevalence of esophageal cancer has recently grown, particularly esophageal squamous cell carcinoma (ESCC). Combining conventional treatment with targeted therapy and immunotherapy has shown unexpectedly positive results in improving the prognosis of patients with ESCC. More study is needed to determine the prognosis for patients with ESCC and establish the appropriate course of treatment. ROS controls different aspects of cell death from signaling to death, and ROS also regulates the tumor environment, affecting various stromal cells that provide metabolic support, blood supply, and immune response to tumors. Although reactive oxygen species (ROS) play an important role in tumorigenesis, it is difficult to reliably predict the effects of ROS-modulating therapies. Methods: This study aimed to establish a ROS-related score (ROSS) model to individually predict the overall survival and therapeutic effects for ESCC patients. Clinical data were derived from the TCGA-ESCA cohort through "UCSC", as well as the whole genome data. The driver ROS genes were identified based on univariate Cox regression. Following that, ROSS was created via a systematic machine-learning pipeline. The association of ROS with immune infiltration and biological function was subsequently assessed by systematic bioinformatics analysis. Finally, we evaluated the predictive efficacy of ROSS for immunotherapy sensitivity using predictive algorithms and real-world immunotherapy cohorts. Results: Patients with significant ROSS had fewer favorable outcomes, according to the data. The proliferation of ESCA cells treated with core ROS gene knocked down was also detected by CCK8. Both univariate and multivariate Cox regression indicated ROSS to be an independent prognostic factor for ESCC patients; however, subgroup analysis eliminated this finding. The functional assay revealed that immune response and cytotoxicity pathways are associated with ROSS, as the subgroup with low ROSS has an active immune microenvironment. Furthermore, patients with low ROSS responded better to chemotherapy, targeted therapy, and immunotherapy. Conclusions: In this study, we systematically analyzed the ROS-related genes in ESCC and developed a ROSS model to assess prognosis and provide guidelines for treatment decisions. This discovery gave rise to a fresh concept for novel therapeutic procedures for the clinical treatment of ESCC.
Venous thromboembolism prophylaxis during neoadjuvant chemotherapy for patients with ovarian cancer.
Authors: Hannah Dysinger McLaughlin, Alli M. Straubhar, Aimee Rolston, Kevin McCool, Melissa Brackmann, Jean Hansen Siedel, Karen McLean, R. Kevin Reynolds, Shitanshu Uppal
Journal: Journal of Clinical Oncology (2023)

5552 Background: The primary objective was to assess the rate of venous thromboembolism (VTE) in patients with ovarian cancer who received neoadjuvant chemotherapy (NACT) following a quality improvement (QI) intervention of routine pharmacologic VTE prophylaxis compared to patients that did not receive prophylaxis. Methods: This is a retrospective cohort study of patients with pathologically confirmed ovarian cancer that received NACT between January 2009 to December 2021 from a single institution. Patients were excluded if VTE was diagnosed prior to initiating NACT. Routine pharmacologic VTE prophylaxis during NACT started in January 2017 following a QI initiative. VTE events were diagnosed by doppler scan of extremities or computed tomography of the chest ordered for symptomatic patients or diagnosed incidentally on routine treatment imaging. Patient factors and perioperative variates of interest were investigated for their association with VTE events through univariate and multivariate models. Results: A total of 290 patients with ovarian cancer received NACT and were included, with 106 of 290 patients (36.5%) receiving pharmacologic prophylaxis during NACT. Rate of VTE prophylaxis prior to the QI intervention was 3.68% (n=5) compared to 65.58% (n=101) after. The rate of VTE during NACT was 11.41% (n=21) without prophylaxis and 2.83% (n=3) with prophylaxis (p=0.013) (Table). The rate of any VTE event from the start of NACT through adjuvant chemotherapy was 20.11% (n=37) without prophylaxis and 4.72% (n=5) with prophylaxis (p&lt;0.01). There was no difference in adverse bleeding events in those that received prophylaxis to those that did not (0% vs 1.32%, p=0.239). On univariate analysis, VTE prophylaxis was associated with a decreased risk of VTE during NACT (OR 0.23; 95% CI: 0.06-0.78) and any VTE during primary treatment (OR 0.19; 95% CI 0.07-0.52). On multivariate analysis, VTE prophylaxis remained significantly associated with reduced VTE rates during NACT and during primary treatment (p=0.02 and p=0.001, respectively). Conclusions: Routine administration of pharmacologic VTE prophylaxis during NACT for patients with ovarian cancer is associated with reduced risk of VTE during NACT and throughout primary treatment and is not associated with adverse bleeding events. [Table: see text]
Real-world survival of older adults with LA SCCHN using SEER-Medicare.
Authors: Summera Qiheng Zhou, Carmen Ng, Rongrong Wang, Greg Gasior, Dustin Schrader, Sujith Baliga, David Fox
Journal: Journal of Clinical Oncology (2023)

e18071 Background: Squamous cell carcinomas of the head and neck (SCCHN) account for around 4% of all types of malignant neoplasms. Roughly 50-67% of patients with SCCHN present with locally advanced (LA) disease and 65% of them relapse after primary therapy. The standard of care for LA SCCHN is definitive therapy (DT), a combination of surgery and or radiation therapy (RT), with or without platinum-based chemotherapy/cetuximab (chemo), that has been shown to optimize long term disease control. Advances in surgery/RT have led to improved outcomes, but there have been no FDA approved therapeutic agents for LA SCCHN since cetuximab in 2006. Our objective was to characterize the real-world overall survival (OS) of older adults with LA SCCHN in the US. Methods: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, a linkage of cancer registry and claims data, to identify patients diagnosed with LA SCCHN (first and only cancer) from 2010 to 2017 who initiated a relevant treatment (treatment initiation date defined as index date) and were continuously enrolled in Medicare Parts A, B, and D from 12 months pre-index until death or 12 months post-index. We categorized DT as: no DT, non-surgical DT (concurrent chemo + RT (cCRT) or chemo followed by RT/cCRT), or surgical DT (surgery then RT/cCRT with or without prior chemo) using Medicare claims. Median OS (mOS) estimates and 95% confidence intervals (CI) were estimated using the Kaplan-Meier method starting from index date. Results: We identified 1052 older adults with LA SCCHN (median age 73 years, 37% female, and 81% non-Hispanic white). Overall, median follow up was 26.4 months and primary tumor sites were 52.6% oropharynx, 44.7% oral cavity, and 2.8% hypopharynx. LA patients overall had a mOS of 39.2 months. mOS was lowest in patients with SCCHN of the hypopharynx. Around 58% of patients received a DT regimen and mOS was lower for patients treated with non-DT vs DT regimens (21.8 vs 60.9 months, respectively). mOS differed between DT regimens (Table). Conclusions: In this descriptive analysis, we found that OS differed by site and receipt of DT and that a large proportion (42%) of patients received non-DT regimens. mOS was lower in patients who received non-DT vs DT. Despite available treatment options, there remains a need for novel therapies that can improve outcomes in LA SCCHN. Future analyses should explore differences in OS between subgroups while adjusting for patient demographic and clinical characteristics. [Table: see text]
Epidemiology of cholangiocarcinoma in Florida, and differences in risk factors between intra- and extra-hepatic cholangiocarcinoma.
Authors: Paulo S. Pinheiro, Hannah M. Cranford, Qinran Liu, Patricia Denise Jones
Journal: Journal of Clinical Oncology (2023)

e16329 Background: Albeit rare, cholangiocarcinoma (CC) is a poorly understood, highly fatal cancer with an incidence rate of less than 2.5 per 100,000 people. For most cases of CC, causes are not known. Here, we use population-based data from the diverse state of Florida to study the most recent incidence rates and trends for intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and measure the prevalence of potential risk factors and preexisting conditions associated with liver cancer including biliary conditions, diabetes, obesity and dyslipidemia, hypertension, smoking, chronic hepatitis C (HCV) and hepatitis B (HBV) infections, alcohol-related disease, and auto-immunes diseases. Methods: We used the Florida Cancer Registry Data on all cases of cholangiocarcinoma (N = 5,096) diagnosed during 2010–2018 (2,930 intra-hepatic, 2,166 extra-hepatic). Data were linked with two other data sources: the Agency for Healthcare Administration and the Department of Viral Hepatitis. Age-adjusted rates by sex were computed, incidence trends using Joinpoint regression and 5-year age-adjusted survival, using lifetable methods, were estimated. Differences in prevalence of risk factors were tested using chi-square tests. Results: Both ICC rates, 1.7 (per 100,000) for males and 1.3 for females, and ECC rates, 1.0 in males and 0.7 in females are relatively low. ICC is currently the fastest increasing cancer at a rate of +7.2% per year in males and +6.5% in females, while ECC trends remain stable. The 5-year survival was 11.0% for ICC (95%CI: 9.2-12.8) and 12.9% (95%CI: 10.5-15.3) for ECC. Overall, conditions such as diabetes type 2 (29%), obesity and dyslipidemia (41%), and hypertension (61%) were highly but equally prevalent in both ICC and ECC. The presence of non-alcohol related cirrhosis (6.0% vs 2.8% for ICC and ECC, respectively), chronic HCV infection (6.6%, 2.0%), and smoking (52.7%, 48.5%) were significantly more prevalent in ICC, while cholangitis of any type (13.5%,26.0%), chronic pancreatitis, auto-immune diseases (all. Conclusions: Currently, ICC is the most rapidly increasing cancer in the US; though, the extent to which better recognition of ICC plays a role in this trend is unknown. ICC and ECC show similarities, but also, differences in the prevalence of specific risk factors and preexisting conditions. The commonly held perception that the increase in metabolic causes (diabetes and obesity), similarly present in both ICC and ECC, are responsible for the current trends is partially challenged by the stable trends in ECC. Given its dismal prognosis, cholangiocarcinoma, especially ICC, requires further research. Funding: This work was supported by Bankhead Coley Grant #20B16 from the Biomedical Research Program of the Department of Health State of Florida.
Association of tumor homologous recombination deficiency (HRD) score with immune checkpoint inhibitor benefit in metastatic clear cell renal cell carcinoma.
Authors: Claud Grigg, Wei Sha, Rupali Bose, Brittany Neelands, Landon Carter Brown, Justin T. Matulay, Peter E. Clark, Earle F Burgess
Journal: Journal of Clinical Oncology (2023)

e16538 Background: Genomic aberrations resulting in homologous recombination repair deficiency (HRD) can be successfully targeted with poly (ADP-ribose) polymerase (PARP) inhibitors. Tumors with HRD also have a higher tumor mutation burden (TMB) and immunogenic phenotypes, prompting PARP inhibitor + immune checkpoint inhibitor (ICI) trials across cancer types. Clear cell renal cell carcinoma (ccRCC) rarely harbors canonical genomic aberrations associated with HRD. However, a “BRCA-like” HRD phenotype can be detected from next-gen DNA- or RNA-sequencing using models trained on tumors with BRCA1/2 bi-allelic loss. We hypothesized that this novel HRD phenotype is associated with ICI benefit in metastatic ccRCC. Methods: Patients with metastatic ccRCC who underwent nephrectomy and were treated with anti-PD-1/L1 ICI monotherapy +/- ipilimumab were identified in an institutional database (N = 52), and outcomes were determined by chart review. Progression free survival (PFS) and overall survival (OS) were calculated from the start date of ICI treatment. Targeted next generation DNA and whole transcriptome sequencing were performed from archived nephrectomy specimens using the Tempus xT platform. HRD scores were calculated using DNA (HRD-DNA) and RNA (HRD-RNA) based methods as previously described (Liebowitz BD et al. BMC Cancer 2022). HRD status was analyzed as a continuous rather than binary variable, as biologically relevant cutoff thresholds have not been established for ccRCC. Multivariable Cox regression models were used to evaluate the association between HRD scores and PFS or OS when demographic/pathologic covariates were adjusted. Results: The cohort was predominantly white (n = 48; 92%) and male (n = 37; 71%) with good performance status (ECOG 0-1: n = 47; 90%). Half (n = 26) were current/former smokers; median age 67 years and BMI 28. Twenty-four (46%) nephrectomies were cytoreductive. Most tumors were staged pT3/4 (85%) and grade 3/4 (90%) including 18 (35%) with sarcomatoid histology. ICI monotherapy or ICI + ipilimumab were received by 32 (62%) and 20 (38%) patients, respectively, in the 1st (40%), 2nd (40%), 3rd (17%), or 4th (2%) line. Median PFS and OS for the cohort were 6.4 months (95% CI 4.4-11.1) and 62.7 months (95% CI 32.8-not applicable). HRD-DNA and HRD-RNA could be calculated for 47 and 46 subjects, respectively. HRD-DNA was not found to be associated with PFS nor OS. High HRD-RNA score was associated with improved PFS (HR 0.92 per unit increase; 95% CI 0.85-1.00, p = 0.052) in the multivariable model, but not OS. Conclusions: High HRD-RNA was associated with longer PFS for metastatic ccRCC patients undergoing ICI-treatment. A “BRCA-like” transcriptomic signature may be predictive of ICI benefit in ccRCC.